Researchers at Johns Hopkins Medicine and the National Cancer Institute have identified a new pathway in Parkinson's disease as well as a potential compound that eases symptoms in mice.
Previous research showed that an enzyme called parkin, which malfunctions in the disease, codes a mass of other proteins for destruction by the cell's recycling machinery. In other words, nonfunctional parkin leads to the buildup of its target proteins. Valina Dawson, director of the Stem Cell Biology and Neuroregeneration Programs at the Johns Hopkins University School of Medicine's Institute for Cell Engineering, and her husband Dr. Ted Dawson, the director of the institute, are trying to shed light on what roles these proteins might play in the disease.
The Dawsons partnered with Debbie Swing and Lino Tessarollo of the National Cancer Institute to develop mice whose genes for a protein called AIMP2--normally tagged for destruction by parkin--could be hyperactivated. The genetically modified mice allowed the researchers to focus on the consequences of too much AIMP2 and set aside the effects of defective parkin and excesses of other proteins.
What the researchers observed was that, as the mice aged, they developed Parkinson's-like symptoms, including the death of dopamine-making cells in the brain. Further investigation showed that AIMP2 was activating a self-destruct pathway called parthanatos, originally discovered by the Dawsons years ago. The team discovered that AIMP2 triggered the pathway by directly interacting with a protein called PARP1, which was up until now believed to respond only to DNA damage, not to signals from other proteins.
The investigators tested a compound that blocks PARP1 on mice with too much AIMP2 and found that the substance protected dopamine-making neurons from dying and prevented behavioral abnormalities similar to those seen in Parkinson's disease in humans. The research was published Aug. 25 online in Nature Neuroscience.
While the results of the study are encouraging, the researchers said they must first do more extensive animal testing, including research with mice whose Parkinson's symptoms don't arise from genetically amped-up AIMP2 production. Ted Dawson and other scientists at Johns Hopkins are also working on finding measurable markers of the disease's severity in order to eventually test new Parkinson's drugs in a clinical trial setting.
- here's the study abstract
- read the press release